The present invention relates to novel phenylheteroalkylamine derivatives, processes for their preparation, compositions containing them and their use in therapy.
Nitric oxide is produced in mammalian cells from L-arginine by the action of specific nitric oxide synthases (NOSs). These enzymes fall into two distinct classesxe2x80x94constitutive NOS (cNOS) and inducible NOS (iNOS). At the present time, two constitutive NOSs and one inducible NOS have been identified. Of the constitutive NOSs, an endothelial enzyme (ecNOS) is involved with smooth muscle relaxation and the regulation of blood pressure and blood flow, whereas the neuronal enzyme (ncNOS) serves as a neurotransmitter and appears to be involved in the regulation of various biological functions such as cerebral ischaemia. Inducible NOS has been particularly implicated in the pathogenesis of inflammatory diseases. Regulation of these enzymes should therefore offer considerable potential in the treatment of a wide variety of disease states (J. E. Macdonald, Ann. Rep. Med. Chem., 1996, 31, 221-230).
Considerable effort has been expended in efforts to identify compounds that act as specific inhibitors of one or more isoforms of the enzyme nitric oxide synthase. The use of such compounds in therapy has also been widely claimed.
According to the present invention, there is provided a compound of formula (I) 
wherein:
X and Y independently represent C1 to 4 alkyl, C1 to 4 alkoxy, halogen, CF3, OCF3, CN, Cxe2x89xa1CH, S(O)mCH3, S(O)pCF3, NO2 or NHCHO;
m and p independently represent an integer 0, 1 or 2;
Z represents H or fluoro;
V represents O, S(O)n or NR3;
W represents C1 to 4 alkyl, C2 to 4 alkenyl, C2 to 4 alkynyl, C3 to 6 cycloalkyl or a 4 to 8 membered saturated heterocyclic ring incorporating one heteroatom selected from O, S and N; any of said groups being optionally further substituted by C1 to 4 alkyl, C1 to 4 alkoxy, C1 to 4 alkylthio, C3 to 6 cycloalkyl; halogen or phenyl; said phenyl group being optionally further substituted by one or more substituents selected independently from halogen, C1 to 4 alkyl, C1 to 4 alkoxy, CF3, OCF3, CN or NO2;
or W represents phenyl or a five or six membered aromatic heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S and N; said phenyl or aromatic heterocyclic ring being optionally substituted by one or more substituents selected independently from halogen, C1 to 4 alkyl, C1 to 4 alkoxy, OH, CN, NO2 or NR4R5; said alkyl or alkoxy group being optionally further substituted by one or more fluorine atoms;
R1 and R2 independently represent H, C1 to 4 alkyl or C3 to 6 cycloalkyl; said alkyl group being optionally substituted by C1 to 4 alkoxy, halogen, hydroxy, NR6R7, phenyl or a five or six membered aromatic or saturated heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S and N; said phenyl or aromatic heterocyclic ring being optionally further substituted by halogen, C1 to 4 alkyl, C1 to 4 alkoxy, CF3, OCF3, CN or NO2;
or the group NR1R2 together represents a 4 to 8 membered saturated azacyclic ring optionally incorporating one further heteroatom selected from O, S or NR8; said ring being optionally substituted by C1 to 4 alkyl, C1 to 4 alkoxy or OH; said alkyl group being optionally substituted by C1 to 4 alkoxy, OH or NR9R10;
or the group NR1 R2 together represents part of a five membered aromatic azacyclic ring optionally incorporating one further N atom;
R3 represents H or C1 to 4 alkyl;
R4, R5, R6, R7, R9 and R10 independently represent H or C1 to 4 alkyl;
R8 represents H or C1 to 6 alkyl; said alkyl group being optionally substituted by C1 to 4 alkoxy, OH, NR11R12, phenyl or a five or six membered aromatic or saturated heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S and N; said phenyl or aromatic heterocyclic ring being optionally further substituted by halogen, C1 to 4 alkyl, C1 to 4 alkoxy, CF3, OCF3, CN or NO2;
R11 and R12 independently represent H or C1 to 4 alkyl;
n represents an integer 0, 1 or 2;
or a pharmaceutically acceptable salt, enantiomer or racemate thereof.
The compounds of formula (I) and their pharmaceutically acceptable salts, enantiomers and racemates have the advantage that they are inhibitors of the enzyme nitric oxide synthase (NOS). In particular, the compounds of formula (I) and their pharmaceutically acceptable salts, enantiomers and racemates have the advantage that they are inhibitors of the inducible isoform of the enzyme nitric oxide synthase (iNOS).
The invention further provides a process for the preparation of compounds of formula (I) or a pharmaceutically acceptable salt, enantiomer or racemate thereof.
According to the invention there is also provided a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer or racemate thereof, for use as a medicament.
Another aspect of the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer or racemate thereof, in the manufacture of a medicament, for the treatment or prophylaxis of diseases or conditions in which inhibition of nitric oxide synthase activity is beneficial.
A more particular aspect of the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer or racemate thereof, in the manufacture of a medicament, for the treatment or prophylaxis of inflammatory disease.
According to the invention, there is also provided a method of treating, or reducing the risk of, diseases or conditions in which inhibition of nitric oxide synthase activity is beneficial which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer or racemate thereof.
More particularly, there is also provided a method of treating, or reducing the risk of, inflammatory disease in a person suffering from or at risk of, said disease, wherein the method comprises administering to the person a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer or racemate thereof.
The compounds of the present invention may also be used advantageously in combination with a second pharmaceutically active substance, particularly in combination with a selective inhibitor of the inducible isoform of cyclooxygenase (COX-2). Thus, in a further aspect of the invention there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer or racemate thereof, in combination with a COX-2 inhibitor for the treatment of inflammation, inflammatory disease and inflammatory related disorders. And there is also provided a method of treating, or reducing the risk of, inflammation, inflammatory disease and inflammatory related disorders in a person suffering from or at risk of, said disease or condition, wherein the method comprises administering to the person a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer or racemate thereof in combination with a COX-2 inhibitor.
In one preferred embodiment, V represents O. In another preferred embodiment, V represents S.
In another preferred embodiment, X and Y independently represent Br, Cl, CH3, CF3 or CN. It is particularly preferred that X represents Cl or CF3. It is also particularly preferred that Y represents Cl, CN or CF3.
Preferably, W represents an optionally substituted five or six membered aromatic heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S and N. Particular examples are those wherein W represents thienyl, furyl, imidazolyl, pyridyl, thiazolyl or triazolyl.
Preferably, R1 and R2 independently represent H or C1 to 4 alkyl optionally substituted by C1 to 4 alkoxy or hydroxy. More preferably, R1 and R2 independently represent H or methyl.
Particular compounds of the invention include:
4-chloro-2-[[(1R)-4-(methylamino)-1-phenylbutyl]oxy]benzonitrile;
R-xcex3-(2,5-dichlorophenoxy)-N-methyl-benzenebutanamine;
4-chloro-2-[[(1R)-1-phenyl-4-(1-pyrrolidinyl)butyl]oxy]-benzonitrile;
4-chloro-2-[[(1R)-4-(4-morpholinyl)-1-phenylbutyl]oxy]-benzonitrile;
4-chloro-2-[[(1R)-4-[ethyl(2-hydroxyethyl)amino]-1-phenylbutyl]oxy]-benzonitrile;
4-chloro-2-[[(1R)-1-phenyl-4-[(3-pyridinylmethyl)amino]butyl]oxy]-benzonitrile;
4-chloro-2-[[(1R)-4-[[2-(1H-imidazol-5-yl)ethyl]amino]-1-phenylbutyl]oxy]-benzonitrile;
4-chloro-2-[[(1R)-4-(1H-imidazol-1-yl)-1-phenylbutyl]oxy]-benzonitrile;
4-chloro-2-[[(1R)-4-[(2-hydroxyethyl)amino]-1-phenylbutyl]oxy]-benzonitrile;
4-chloro-2-[[(1R)-4-(cyclopropylamino)-1-phenylbutyl]oxy]-benzonitrile;
4-chloro-2-[[(1R)-4-[(3-hydroxypropyl)amino]-1-phenylbutyl]oxy]-benzonitrile;
4-chloro-2-[[(1R)-4-[[(1R)-2-hydroxy-1-methylethyl]amino]-1-phenylbutyl]oxy]-benzonitrile;
4-chloro-2-[[(1R)-4-[[(1S)-2-hydroxy-1-methylethyl]amino]-1-phenylbutyl]oxo]-benzonitrile;
4-chloro-2-[4-[[(2-fluoroethyl)amino]-1-phenylbutyl]oxy]-benzonitrile;
R-xcex4-(2,5-dichlorophenoxy)-4-fluoro-N-methyl-benzenebutanamine;
S-xcex4-(2,5-dichlorophenoxy)-4-fluoro-N-methyl-benzenebutanamine;
R-xcex3-(2,5-dichlorophenoxy)-N,4-dimethyl-benzenebutanamine;
S-xcex3-(2,5-dichlorophenoxy)-N,4-dimethyl-benzenebutanamine;
xcex4-(2,5-dichlorophenoxy)-N-methyl-2-thiophenebutanamine;
2-[(4-amino-1-phenylbutyl)amino]-4-chloro-benzonitrile;
2-[[1-(3-aminopropyl)-3-methylbutyl]amino]-4-(trifluoromethyl) benzonitrile;
2-[[4-(2,5-dichlorophenoxy)-4-phenylbutyl]methylamino]ethanol;
1-[4-(2,5-dichlorophenoxy)-4-phenylbutyl]-4-piperidinol;
1-[4-(2,5-dichlorophenoxy)-4-phenylbutyl]piperazine;
1-[4-(2,5-dichlorophenoxy)-4-(2-thienyl)butyl]4-methyl-piperazine;
4-chloro-2-[4-(methylamino)-1-(3-thienyl)butoxy]-benzonitrile;
4-chloro-2-[1-(3-furanyl)-4-(methylamino)butoxy]benzonitrile;
2-[4-amino-1-(3-furanyl)butoxy]-4-chlorobenzonitrile;
4-chloro-2-[1-(2-furanyl)-4-(methylamino)butoxy]benzonitrile;
2-[[(1R)-4-amino-1-(1-methyl-1H-imidazol-2-yl)butyl]oxy]-4-chloro-5-fluorobenzonitrile;
4-chloro-2-[4-(methylamino)-1-(2-pyridinyl)butoxy]benzonitrile;
4-chloro-5-fluoro-2-[4-(methylamino)-1-(2-pyridinyl)butoxy]benzonitrile;
4-chloro-2-[4-(ethylamino)-1-(2-pyridinyl)butoxy]benzonitrile;
2-[4-amino-1-(3-pyridinyl)butoxy]-4-chloro-benzonitrile;
4-chloro-2-[4-(methylamino)-1-(3-pyridinyl)butoxy]-benzonitrile;
4-chloro-2-[4-(ethylamino)-1-(4-pyridinyl)butoxy]-benzonitrile;
4-chloro-2-[4-(methylamino)-1-(4-pyridinyl)butoxy]benzonitrile;
4-chloro-2-[4-[(2-hydroxyethyl)amino]-1-(4-pyridinyl)butoxy]benzonitrile;
2-[4-amino-1-(2-methoxy-3-pyridinyl)butoxy]-4-chloro-benzonitrile;
2-[4-amino-1-(1,2-dihydro-2-oxo-3-pyridinyl)butoxy]-4-chlorobenzonitrile;
2-[[(1R)-4-amino-1-(3-furanyl)butyl]oxy]-4-chloro-5-fluoro-benzonitrile;
4-chloro-5-fluoro-2-[[(1R)-1-(3-furanyl)-4-(methylamino)butyl]oxy]benzonitrile;
2-[4-amino-1-(2-thiazolyl)butoxy]-4-chlorobenzonitrile;
xcex4-[2-chloro-5-(trifluoromethyl)phenoxy]-2-thiazolebutanamine;
2-[4-amino-1-(1-methyl-1H-1,2,4-triazole-5-yl)butoxy-4-chlorobenzonitrile;
xcex4-[2-chloro-5-(trifluoromethyl)phenoxy]-1-methyl-1H-1,2,4-triazole-5-butanamine;
and pharmaceutically acceptable salts, enantiomers or racemates thereof.
Unless otherwise indicated, the term xe2x80x9cC1 to 4 alkylxe2x80x9d referred to herein denotes a straight or branched chain alkyl group having from 1 to 4 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl.
The term xe2x80x9cC1 to 6 alkylxe2x80x9d is to be interpreted analogously.
Unless otherwise indicated, the term xe2x80x9cC3 to 6 cycloalkylxe2x80x9d referred to herein denotes a cycloalkyl group having from 3 to 6 carbon atoms. Examples of such groups include cyclopropyl, cyclopentyl and cyclohexyl.
Unless otherwise indicated, the term xe2x80x9cC2 to 4 alkenylxe2x80x9d referred to herein denotes a straight or branched chain alkyl group having from 2 to 4 carbon atoms incorporating at least one carbon-carbon double bond. Examples of such groups include ethenyl, propenyl and butenyl.
Unless otherwise indicated, the term xe2x80x9cC2 to 4 alkynylxe2x80x9d referred to herein denotes a straight or branched chain alkyl group having from 2 to 4 carbon atoms incorporating at least one carbon-carbon triple bond. Examples of such groups include ethynyl, propynyl, and butynyl.
Unless otherwise indicated, the term xe2x80x9cC1 to 4 alkoxyxe2x80x9d referred to herein denotes a straight or branched chain alkoxy group having from 1 to 4 carbon atoms. Examples of such groups include methoxy, ethoxy, n-propoxy, i-propoxy and t-butoxy.
The term xe2x80x9cC1 to 4 alkylthioxe2x80x9d is to be interpreted analogously.
Unless otherwise indicated, the term xe2x80x9chalogenxe2x80x9d referred to herein denotes fluoro, chloro, bromo and iodo.
Examples of a 4 to 8 membered saturated azacyclic ring optionally incorporating one further heteroatom selected from O, S or N include pyrrolidine, piperidine, piperazine, morpholine and perhydroazepine.
Examples of a 4 to 8 membered saturated heterocyclic ring incorporating one heteroatom selected from O, S or N include pyrrolidine, piperidine, tetrahydrofuran and perhydroazepine.
Examples of a five or six membered aromatic heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S and N include furan, thiophene, pyridine, thiazole, imidazole, oxazole, triazole, oxadiazole, thiadiazole and pyrimidine.
Examples of a five or six membered saturated heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S and N include pyrrolidine, tetrahydrofuran, piperidine and piperazine.
Examples of a xe2x80x9cC1 to 4 alkyl or C1 to 4 alkoxy optionally further substituted by one or more fluorine atomsxe2x80x9d include CF3, CF3CF2, CF3CH2, CH2FCH2, CH3CF2, CF3CH2CH2, OCF3 and OCH2CF3.
Examples of a five membered aromatic azacyclic ring optionally incorporating one further N atom include pyrrole and imidazole.
According to the invention, we further provide a process for the preparation of compounds of formula (I), or a pharmaceutically acceptable salt, enantiomer or racemate thereof which comprises:
(a) reaction of a compound of formula (II) 
wherein X, Y, V and Z are as defined in formula (I), with a compound of formula (III) 
wherein W, R1 and R2 are as defined in formula (I); or
(b) reaction of a compound of formula (IV) 
wherein X, Y and Z are as defined in formula (I) and L1 represents a leaving group, with a compound of formula (V) 
wherein R1, R2, V and W are as defined in formula (I); or
(c) reaction of a compound of formula (VI) 
wherein X, Y, V, W and Z are as defined in formula (I) and L2 is a leaving group, with a compound of formula (VII)
HNR1R2xe2x80x83xe2x80x83(VII)
wherein R1 and R2 are as defined in formula (I); or
(d) reaction of a compound of formula (II) 
wherein X, Y, V and Z are as defined in formula (I), with a compound of formula (VIII) 
wherein R1, R2 and W are as defined in formula (I) and L3 is a leaving group; or
(e) reduction of a compound of formula (IX) 
wherein X, Y, V, W and Z are as defined in formula (I) and G represents a group that upon reduction is converted into a group NR1R2; and where necessary converting the resultant compound of formula (I), or another salt thereof, into a pharmaceutically acceptable salt thereof; or converting the resultant compound of formula (I) into a further compound of formula (I); and where desired converting the is resultant compound of formula (I) into an optical isomer thereof.
In process (a), the reactants (II) and (III) are coupled together in a suitable inert solvent such as tetrahydrofuran using, for example, Mitsunobu conditions. Thus, for example, the reactants are treated with a phosphine derivative and an azo derivative at a suitable temperature, generally between 0xc2x0 C. and the boiling point of the solvent. Suitable phosphine derivatives include triphenylphosphine and tributylphosphine. Suitable azo derivatives include diethyl azodicarboxylate, diisopropyl azodicarboxylate and 1,1xe2x80x2-(azodicarbonyl)dipiperidine.
In process (b), the reaction is performed by treating a nucleophile of formula (V) with an electrophile of formula (IV) in an inert solvent. Suitable leaving groups L1 include halides, particularly fluoride. The reaction is generally performed in the presence of a non-nucleophilic base such as sodium hydride. Suitable organic solvents are those such as N-methyl-2-pyrrolidinone, tetrahydrofuran and dimethylsulfoxide. The reaction is generally conducted at a temperature between 0xc2x0 C. and the boiling point of the solvent.
Alternatively, in process (b), the reaction will take place using an appropriate palladium source such as palladium (II) acetate in the presence of a suitable phosphine ligand such as BINAP.
In process (c), the amination reaction is performed by reacting a compound of formula (VI) with an amine (VII) in an inert solvent. Suitable leaving groups L2 include sulfonate, trifluorosulfonate, tosylate and halides selected from the group chloride, bromide or iodide. The nucleophile can be a primary or secondary amine in the presence of a base. This base can be either an excess of the amine nucleophile or can be an additive to the reaction mixture. Potential basic additives are metal carbonate, especially alkali metal carbonates, metal oxides and hydroxides, and tertiary amine bases. Suitable organic solvents are those such as acetonitrile, dioxane, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, tetrahydrofuran, dimethylsulfoxide, sulfolane and C1 to 4 alcohols.
In process (d), the reaction is performed by treating a nucleophile of formula (II) with an. electrophile of formula (VIII) in an inert solvent. Suitable leaving groups L3 include halides, particularly chloride or bromide. The reaction is generally performed in the presence of a non-nucleophilic base such as sodium hydride. Suitable organic solvents are those such as N-methyl-2-pyrrolidinone, tetrahydrofuran and dimethylsulfoxide. The reaction is generally conducted at a temperature between 0xc2x0 C. and the boiling point of the solvent.
In process (e), G preferably represents an azido (N3) group. The required reduction may then be achieved by treating a compound of formula (IX) with a suitable reducing agent such as Sn(II) or triphenylphosphine. Preferably the reducing agent is triphenylphosphine and the reduction is carried out in a suitable inert solvent such as tetrahydrofuran.
It will be apparent to a person skilled in the art that in the above processes it may be desirable or necessary to protect an amine, hydroxyl or other potentially reactive group. Suitable protecting groups and details of processes for adding and removing such groups may be found by reference to the standard text xe2x80x9cProtecting Groups in Organic Synthesisxe2x80x9d, 2nd Edition (1991) by Greene and Wuts. In one preferred embodiment, amine groups are protected as carbamate derivatives, for example, as t-butyloxycarbamates. Thus, compounds of formula (I) in which R1 is H are conveniently prepared by removal of a carbamate protecting group from a corresponding compound of formula (I) wherein R1 is a carbamate group, especially a t-butyloxycarbamate group. Removal of the carbamate group is conveniently effected using hydrogen chloride in dioxan.
The present invention includes compounds of formula (I) in the form of salts, in particular acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable although salts of non-pharmaceutically acceptable acids may be of utility in the preparation and purification of the compound in question. Thus, preferred salts include those formed from hydrochloric, hydrobromic, sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids.
Salts of compounds of formula (I) may be formed by reacting the free base, or a salt, enantiomer or racemate thereof, with one or more equivalents of the appropriate acid. The reaction may be carried out in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is soluble, for example, water, dioxane, ethanol, tetrahydrofuran or diethyl ether, or a mixture of solvents, which may be removed in vacuo or by freeze drying. The reaction may also be a metathetical process or it may be carried out on an ion exchange resin.
Certain novel intermediates of formulae (III), (V), (VI), (VIII) and (IX) form another aspect of the invention.
Compounds of formula (III) may be prepared by reaction of a compound of formula (X) 
wherein R1 and R2 are as defined in formula (I), with an organometallic derivative, Wxe2x80x94M, wherein W is as defined in formula (I) and M represents a metallic residue such as lithium or magnesium-halide, or M represents a silyl residue such as SiMe3.
Compounds of formula (IX) may be prepared by:
(a) reacting a compound of formula (II), as defined above, with a compound of formula (XI) 
wherein W and G are as defined above; or
(b) reacting a compound of formula (IV), as defined above, with a compound of formula (XII) 
wherein V, W and G are as defined above.
Compounds of formulae (II), (IV), (VII), (X), (XI) and (XII) are either known or may be prepared using known methods. Some such methods are illustrated within the Examples that are included herein. Other suitable methods will be readily apparent to the man skilled in the art.
Intermediate compounds may be used as such or in protected form. Protecting groups and details of processes for their removal may be found by reference to the standard text xe2x80x9cProtecting Groups in Organic Synthesisxe2x80x9d, 2nd Edition (1991) by Greene and Wuts.
The compounds of the invention and intermediates thereto may be isolated from their reaction mixtures and, if necessary further purified, by using standard techniques.
The compounds of formula I may exist in enantiomeric forms. Therefore, all enantiomers, diastereomers, racemates and mixtures thereof are included within the scope of the invention. The various optical isomers may be isolated by separation of a racemic mixture of the compounds using conventional techniques, for example, fractional crystallisation, or HPLC.
Intermediate compounds may also exist in enantiomeric forms and may be used as purified enantiomers, diastereomers, racemates or mixtures.
The compounds of formula (I), and their pharmaceutically acceptable salts, enantiomers and racemates, are useful because they possess pharmacological activity in animals. In particular, the compounds are active as inhibitors of the enzyme nitric oxide synthase. More particularly, they are inhibitors of the inducible isoform of the enzyme nitric oxide synthase and as such are predicted to be useful in therapy, for example, as anti-inflammatory agents. They may also have utility as inhibitors of the neuronal isoform of the enzyme nitric oxide synthase.
The compounds and their pharmaceutically acceptable salts, enantiomers and racemates are indicated for use in the treatment or prophylaxis of diseases or conditions in which synthesis or oversynthesis of nitric oxide synthase forms a contributory part. In particular, the compounds are indicated for use in the treatment of inflammatory conditions in mammals including man.
Conditions that may be specifically mentioned are:
osteoarthritis, rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis and other arthritic conditions, inflamed joints;
eczema, psoriasis, dermatitis or other inflammatory skin conditions such as sunburn;
inflammatory eye conditions including uveitis, glaucoma and conjunctivitis;
lung disorders in which inflammation is involved, for example, asthma, bronchitis, chronic obstructive pulmonary disease, pigeon fancier""s disease, farmer""s lung, acute respiratory distress syndrome;
bacteraemia, endotoxaemia (septic shock), aphthous ulcers, gingivitis, pyresis, pain, meningitis and pancreatitis;
conditions of the gastrointestinal tract including inflammatory bowel disease, Crohn""s disease, atrophic gastritis, gastritis varialoforme, ulcerative colitis, coeliac disease, regional ileitis, peptic ulceration, irritable bowel syndrome, reflux oesophagitis, damage to the gastrointestinal tract resulting from infections by, for example, Helicobacter pylori, or from treatments with non-steroidal anti-inflammatory drugs;
and other conditions associated with inflammation.
The compounds will also be useful in the treatment and alleviation of acute pain or persistent inflammatory pain or neuropathic pain or pain of a central origin.
We are particularly interested in the conditions inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, chronic obstructive pulmonary disease and pain.
The compounds of formula (I) and their pharmaceutically acceptable salts, enantiomers and racemates may also be useful in the treatment or prophylaxis of diseases or conditions in addition to those mentioned above. For example, the compounds may be useful in the treatment of atherosclerosis, cystic fibrosis, hypotension associated with septic and/or toxic shock, in the treatment of dysfunction of the immune system, as an adjuvant to short-term immunosuppression in organ transplant therapy, in the control of onset of diabetes, in the maintenance of pancreatic function in diabetes, in the treatment of vascular complications associated with diabetes and in co-therapy with cytokines, for example TNF or interleukins.
The compounds of formula (I) may also be useful in the treatment of hypoxia, for example in cases of cardiac arrest and stroke, neurodegenerative disorders including nerve degeneration and/or nerve necrosis in disorders such as ischaemia, hypoxia, hypoglycaemia, epilepsy, and in external wounds (such as spinal cord and head injury), hyperbaric oxygen convulsions and toxicity, dementia, for example pre-senile dementia, Alzheimer""s disease and AIDS-related dementia, Sydenham""s chorea, Parkinson""s disease, Tourette""s Syndrome, Huntington""s disease, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, Korsakoff""s disease, imbecility relating to a cerebral vessel disorder, sleeping disorders, schizophrenia, depression, pain, autism, seasonal affective disorder, jet-lag, depression or other symptoms associated with Premenstrual Syndrome (PMS), anxiety and septic shock. Compounds of formula (I) may also be expected to show activity in the prevention and reversal of drug addiction or tolerance such as tolerance to opiates and diazepines, treatment of drug addiction, treatment of migraine and other vascular headaches, neurogenic inflammation, in the treatment of gastrointestinal motility disorders, cancer and in the induction of labour.
We are particularly interested in the conditions stroke, Alzheimer""s disease, Parkinson""s disease, multiple sclerosis, schizophrenia, migraine, cancer, septic shock and pain.
Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
For the above mentioned therapeutic indications, the dosage administered will, of course, vary with the compound employed, the mode of administration and the treatment desired. However, in general, satisfactory results are obtained when the compounds are administered at a dosage of the solid form of between 1 mg and 2000 mg per day.
The compounds of formula (I), and pharmaceutically acceptable derivatives thereof, may be used on their own, or in the form of appropriate pharmaceutical compositions in which the compound of derivative is in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. Administration may be by, but is not limited to, enteral (including oral, sublingual or rectal), intranasal, intravenous, topical or other parenteral routes. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, xe2x80x9cPharmaceuticalsxe2x80x94The Science of Dosage Form Designsxe2x80x9d, M. E. Aulton, Churchill Livingstone, 1988. The pharmaceutical composition preferably comprises less than 80% and more preferably less than 50% of a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer or racemate thereof.
There is also provided a process for the preparation of such a pharmaceutical composition which comprises mixing the ingredients.
The compounds of formula (I), and pharmaceutically acceptable derivatives thereof, may also be advantageously used in combination with a COX-2 inhibitor. Particularly preferred COX-2 inhibitors are Celecoxib and MK-966. The NOS inhibitor and the COX-2 inhibitor may either be formulated together within the same pharmaceutical composition for administration in a single dosage unit, or each component may be individually formulated such that separate dosages may be administered either simultaneously or sequentially.
The invention is illustrated, but in no way limited, by the following examples: